Available online at www.sciencedirect.com Binding to protein surfaces by supramolecular multivalent scaffolds Vera Martos 1,2 , Pilar Castren ˜o 1 , Julia ´ n Valero 1,3 and Javier de Mendoza 1,2 Multivalency plays a pivotal role in biological recognition, particularly at protein–protein and protein–carbohydrate interaction sites. Scaffolds of diverse structure, flexibility, and valency are gaining increasing biomedical importance in the development of artificial multivalent ligands for these interfaces. Relevant examples range from small C 4 symmetric calix[4]arenes and porphyrin ligands, which may achieve nanomolar affinity for protein surfaces of pharmaceutical interest, to large-sized dendrimers that provide promising adherence-inhibition for toxins and other relevant lectins. In addition, highly flexible supramolecular platforms like rotaxanes and polymers have been proposed as challenging alternatives to more rigid designs. Finally, nanoparticles are being exploited for this aim as they present important advantages from the biological and synthetic points of view. Addresses 1 Institute of Chemical Research of Catalonia (ICIQ), Avda. Paı¨sos Catalans 16, 43007 Tarragona, Spain 2 Universidad Auto ´ noma de Madrid, Cantoblanco, 28049 Madrid, Spain 3 Universitat Rovira i Virgili, Av. Paı ¨sos Catalans 5-7, 43007 Tarragona, Spain Corresponding author: de Mendoza, Javier (jmendoza@iciq.es) Current Opinion in Chemical Biology 2008, 12:698–706 This review comes from a themed issue on Model Systems Edited by Helma Wennemers and Ronald T. Raines Available online 16th September 2008 1367-5931/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.cbpa.2008.08.024 Introduction to multivalency and protein surface binding Protein surfaces are challenging targets in drug design because of their relatively large solvated surfaces (ca. 750–1500 A ˚ 2 ) and their shallow and featureless shape, as compared to the well-defined pockets seen in enzyme active sites. Moreover, the binding to a protein surface is rendered difficult by the noncontiguity of ‘hot spots’ [1]. At the edge between biochemistry and supramolecular chemistry, multivalency plays a crucial role in this sort of recognition events [2,3  ]. It refers to multiple noncova- lent interactions between a multiple ligand-containing scaffold and a target with multiple recognition sites, a common case in biological processes such as immunologic response, cell membrane adherence, signal transduction, and several enzymatic systems. Instead of improving the strength of each interaction, nature often uses multiva- lency to increase binding affinity in a well-defined and efficient manner by just increasing the number of ligands and receptors. Supramolecular chemistry brings into play the multi- valency concept to construct higher and defined chemi- cal architectures, giving rise to new nanomaterials and molecular devices. Additionally, it provides theoretical and experimental solutions to better understand the multivalent processes at the biological level, by means of useful concepts such as complementarity, selfassem- bly, cooperativity, molecular recognition, effective molarity (EM), and effective concentration (Ceff) [4]. To this aim, it is essential to clearly distinguish between cooperativity and multivalency [5]. Modulation of the binding affinity of a receptor mediated by a previous recognition event in the same molecule is related to cooperativity, whereas multivalency is related to the Ceff concept, accounting for the probability of an interaction between ligand and receptor [6]. EM, another related concept, refers to the equilibrium between intermole- cular and intramolecular processes occurring in chem- istry [7]. From the molecular point of view [8  ], the length and flexibility of the linker(s), the strength of the noncovalent forces involved, the number of binding elements, or the conformational freedom are the key elements to modu- late these parameters. In this brief account, we review some recent and relevant examples involving multivalency in protein surfaces, where supramolecular chemistry can provide a general understanding about how the processes take place. Supramolecular multivalent scaffolds Multivalent ligands present multiple copies of a recog- nition element (RE) that spans from a central scaffold. The RE can be a carbohydrate, a peptide, or a small molecule binding to a receptor. However, the nature of the supramolecular scaffold and its attached REs — their shape, valency, orientation, and flexibility — greatly influences the binding ability. We will distinguish low- valency scaffolds from those based on high-valency scaf- folds (Figure 1). Current Opinion in Chemical Biology 2008, 12:698–706 www.sciencedirect.com